1. Field of the Invention
The invention relates to a process for preparing aryl- and heteroarylacetic acids and derivatives thereof by reaction of aryl or heteroaryl halides with malonic diesters in the presence of a palladium catalyst, of one or more bases and optionally of a phase transfer catalyst. This process enables the preparation of a multitude of functionalized aryl- and heteroarylacetic acids and derivatives thereof, especially also the preparation of arylacetic acids with sterically demanding substituents.
2. Description of Related Art
Typically, phenylacetic acid derivatives are prepared in multistage syntheses, most of which have low group tolerance. The preparation can be effected, for example, proceeding from acetophenones by a Willgerodt-Kindler reaction (see, for example, H. E. Zaugg et al., J. Amer. Chem. Soc. 70 (1948) 3224-8). In this method, however, large amounts of sulphur-containing wastes arise. Moreover, volatile sulphur compounds with a high level of odour nuisance can occur.
A further method for preparing arylacetic acids proceeds from benzyl bromides or chlorides. Sodium cyanide, for example, is used to prepare the corresponding nitrites therefrom, and these are subsequently hydrolysed. The benzyl bromides or chlorides required can be obtained, for example, by bromo- or chloromethylation of
the corresponding aromatics. However, a disadvantage here is that the occurrence of highly carcinogenic compounds such as bis(chloromethyl) ether or bis(bromomethyl) ether cannot be ruled out, and so a high degree of safety measures has to be implemented in industry. Moreover, the halomethylation of substituted aromatics in many cases leads to isomer mixtures.
The carbonylation of benzyl halides in the presence of alcohols likewise gives phenylacetic esters. The already mentioned limited availability of benzyl halides and the need to use toxic CO gas, in some cases even under elevated pressure, are further disadvantages of this process.
There has also already been a disclosure of ketalizing a-chloroacetophenones and then subjecting the ketals to a rearrangement reaction (C. Giordano et al., Angew. Chem. 96 (1984) 413-9). The a-chloroacetophenones are obtained either by chlorination of acetophenones or directly by a Friedel-Crafts acylation of the aromatic in question with chloroacetyl chloride. This again gives rise to the disadvantage that the Friedel-Crafts acylations of substituted aromatics frequently proceed unselectively.
A further known method for preparing phenylacetic acids consists in diazotizing a corresponding aniline in the first step, reacting the resulting diazonium compound with vinylidene chloride in the second step, and then reacting the trichloro- or bromodichloroethyl compound thus obtained with water or alcohols in the third step to give the arylacetic acid or esters thereof (see, for example, V M. Naidan and A. V Dombrovskii, Zhurnal Obshchei Khimii 34 (1984) 1469-73; EP-A-835243). This reaction, however, generally affords good yields only with those anilines which bear electron-withdrawing radicals on the aromatic and in which the amino group is not sterically blocked.
Additionally known is the reaction of bromobenzenes with chloroacetic acid derivatives in the presence of stoichiometric amounts of silver or copper at 180-200° C. Disadvantages of this process are the high temperature, which rules out use in the case of thermally sensitive compounds, the low yield and the use of stoichiometric amounts of metals which are costly and difficult to work up.
The reaction of aryl-Grignard compounds with α-haloacetic acid derivatives likewise leads to phenylacetic acid derivatives. A disadvantage, however, is the extremely limited tolerance of functional groups, which results from the use of highly reactive Grignard compounds which are difficult to handle.
Alternatives to the processes mentioned which have also been described are cross-couplings of aryl halides with Reformatsky reagents, tin enolates, copper enolates and other enolates, or ketene acetals (see, for example, J. Am. Chem. Soc. 1959, 81, 1627-1630; J. Organomet. Chem. 1979, 177, 273-281; Synth. Comm. 1987, 17, 1389-1402; Bull. Chem. Soc. Jpn. 1985, 58, 3383-3384; J. Org. Chem. 1993, 58, 7606-7607; J. Chem. Soc. Perkin 1 1993, 2433-2440; J. Am. Chem. Soc. 1975, 97, 2507-2517; J. Am. Chem. Soc. 1977, 99, 4833-4835; J. Am. Chem. Soc. 1999, 121, 1473-78; J. Org. Chem. 1991, 56, 261-263, Heterocycles 1993, 36, 2509-2512, Tetrahedron Lett. 1998, 39, 8807-8810). However, the applicability of these processes is limited. For instance, Reformatsky reagents and ketene acetals are difficult to prepare and handle. The use of tin compounds is disadvantageous for toxicological reasons, and the use of stoichiometric amounts of copper causes considerable costs in disposal. The use of enolates is generally possible only when no further enolizable groups are present in the molecule. For example, ketones are therefore ruled out as substrates for such processes. Some electrochemical processes are likewise known (Synthesis 1990, 369-381; J. Org. Chem. 1996, 61, 1748-1755), but these processes are disadvantageous due to the complex reaction regime and the low space-time yields.
Likewise already known is a method for preparing phenylacetic acid derivatives by a palladium-catalysed coupling reaction between arylboronic acids and ethyl bromoacetate (Chem. Commun. 2001, 660-70; DE-A-10111262). However, this process requires the preparation of the boronic acids, typically from the corresponding aryl or heteroaryl halides. Moreover, it has not been possible to date to use this preparation of sterically demanding, for example 2,6-disubstituted, phenylacetic acid derivatives. Chem. Commun. 2001, 660-70 states that sterically hindered arylboronic acids can also be converted efficiently under the conditions described therein. However, the examples contain only 2-tolylboronic acid as a sterically hindered substrate. Arylboronic acids with greater steric hindrance, for example 2,6-dialkylphenylboronic acids, are not described.
A further known method is that of the palladium- or copper-catalysed coupling reaction of aryl halides with malonic esters or β-keto esters, followed by a thermally induced dealkoxycarbonylation or retro-Claisen condensation. This involved reacting aryl iodides and activated aryl bromides with diethyl malonate in the presence of a palladium catalyst and 10 equivalents of very expensive caesium carbonate, and reaction times of up to 76 hours were needed (Chem. Commun. 2001, 2704-2705). Higher yields with shorter reaction times are possible, but these require the use of very specific N-heterocyclic carbene ligands which can be prepared only with difficulty; in addition, the expensive caesium carbonate is used here too (Tetrahedron Lett. 2004, 45, 5823-5825). The palladium- or copper-catalysed arylation of acetoacetic esters, followed by an in situ deacetylation, ultimately only has a narrow range of application; moreover, the deacetylation is frequently incomplete, which results in unsatisfactory yields of arylacetic esters (Tetrahedron Lett. 2004, 45, 4261-4264; Tetrahedron Lett. 2007, 48, 3289-3293).
All methods which have become known to date for preparing phenylacetic acid derivatives, more particularly also those with sterically demanding substitution, accordingly have shortcomings and disadvantages, some of them considerable, which complicate the use thereof. Since phenylacetic acids in general, and among them specifically also those with sterically demanding substitution, are important precursors, for example for active ingredients in crop protection, there is a need for a technically simple and highly efficient method for preparing such compounds.